Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Sjursen, Wenche; McPhillips, Mary; Scott, Rodney J.; Talseth‐Palmer, Bente A.

doi:10.1002/mgg3.198

Cited by 17 publications

(18 citation statements)

References 41 publications

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“…Interestingly, the clinicopathological features of path_MMR carriers described in Latin America families are in accordance with other studies, e.g. the AMSII criteria were fulfilled by 64% of the path_MMR carriers [ 37 , 77 ].…”

Section: Discussionsupporting

confidence: 89%

“…According to our data, the contribution from the different MMR genes is apparently slightly higher for MLH1 and MSH2 and lower for MSH6 and PMS2 when comparing to the InSIGHT database and international reports. It is possible that this pattern reflects the recent inclusion of MSH6, PMS2 and EPCAM in LS genetic testing in Latin America molecular diagnostic laboratories but could also reflect population structure [ 32 , 48 , 76 , 77 ]. Interestingly, the clinicopathological features of path_MMR carriers described in Latin America families are in accordance with other studies, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…In this scenario, published family history data from Paraguay, Peru, Brazil and Mexico suggest its use as a triage tool together with IHC and MSI to identify and stratify genetic risk in these populations [ 19 ]. However, awareness of hereditary cancer among clinicians involved in diagnosis and treatment of CRC is currently low, and families actually meeting the clinical criteria may not be identified [ 77 ]. In addition, the average life expectancy in Latin America and the Caribbean is 75 years and inequalities persist among and within the countries ( www.paho.org ).…”

Section: Discussionmentioning

confidence: 99%

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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

et al. 2017

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BackgroundGenetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. MethodsEleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.ResultsWe performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.ConclusionThe Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

et al. 2017

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“…As in the study by Snowsill et al, 4 the proportions for each LS mutation were taken from the supplementary evidence in the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) review, 42 which stated that, for all true LS-positive patients, 32% have a MLH1 mutation, 39% have a MSH2 mutation, 14% have a MSH6 mutation and 15% have a PMS2 mutation ( Table 28). Reported family registry data can differ significantly from these values, particularly with respect to the proportion of PMS2 mutations identified 91,94,95 (see Table 28). This may potentially be because of PMS2 testing having historically occurred less in current practice than in the trials on which the EGAPP review based its values.…”

Section: Prevalence Of Lynch Syndromementioning

confidence: 99%

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Snowsill

Coelho

Huxley

et al. 2017

Health Technol Assess

112

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BackgroundInherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests – microsatellite instability (MSI) and MMR immunohistochemistry (IHC) – are used in CRC patients to identify individuals at high risk of LS for genetic testing.MLH1(MutL homologue 1) promoter methylation andBRAFV600E testing can be conducted on tumour material to rule out certain sporadic cancers.ObjectivesTo investigate whether testing for LS in CRC patients using MSI or IHC (with or withoutMLH1promoter methylation testing andBRAFV600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources.Review methodsSystematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors.ResultsTen studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC,BRAFV600E andMLH1promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective.LimitationsMost of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted.ConclusionsSystematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients.Study registrationThis study is registered as PROSPERO CRD42016033879.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…The majority of Lynch syndrome cases (69%-90%) arise from germ-line MLH1 and MSH2 mutations; carriers of MSH6 and PMS2 mutations account for the rest [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Identification and verification of a pathogenic MLH1 mutation c.1145dupA in a Lynch syndrome family

et al. 2017

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Lynch syndrome (LS), an autosomal-dominant disorder with an increased risk of predominantly colorectal and endometrial cancers, is caused by germ-line mutations in mismatch repair genes. The identification of germ-line mutations that predispose to cancer is important to further our understanding of tumorigenesis, guide patient management and inform the best practice for healthcare. A 45-year-old woman with atypical endometrial hyperplasia who suffered colon cancer at the age of 30 years underwent hysterectomy and genetic counseling. Pedigree analysis revealed her family fulfilling the Amsterdam I criteria. Next-generation sequencing was offered to the patient. A mutation in the MLH1 gene, c.1145dupA, was identified and verified by Sanger sequencing. In addition, her nine family members were tested for the mutation. Two were affected (colon cancer at the age of 43 years and 45 years) and one healthy relative carried the same mutation in the MLH1 gene. The mutation resulted in a frame-shift (p.Met383Aspfs*12) located in exon12, as well as a polypeptide truncation of 393 amino acids by the formation of a premature stop codon. An immunohistochemistry analysis of endometrial hyperplasia tissues revealed defects in MLH1 and PMS2 protein expression in the patient. Based on the 2015 American College of Medical Genetics and Genomics (ACMG ) guideline, we report this MLH1 c.1145dupA variation to be a pathogenic mutation that contributes to a strongly increased cancer risk in this LS family. Proper screening suggestions were offered to the three affected patients and the healthy carrier. To the best of our knowledge, this germ-line mutation of MLH1 was previously submitted to the Leiden Open Variation Database (LOVD) database, but no comprehensive evidence or supporting observations were reported previously in the literature. The present report found a single nucleotide insertion in exon12 of the MLH1 gene, which can be considered causative of Lynch phenotype. Moreover, identification of individuals at risk for hereditary syndromes is important, as they can benefit from genetic counseling and increased surveillance.

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Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Cited by 17 publications

References 41 publications

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Identification and verification of a pathogenic MLH1 mutation c.1145dupA in a Lynch syndrome family

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